Skin wounds are damage of surface tissues such as rupture, abrasion, surgical incision, skin ulcer or burn. General treatment of these skin wounds is to give first aid to wounded sites and then to wait spontaneous recovery due to restoration of a living body.
However, such spontaneous recovery requires a long period until restoration, and pains also continue. Accordingly, it is desirable to promote wound healing positively by administering therapeutic agents for wounds to the wounded sites.
Since new epithelial tissues and connective tissues are formed by migration and proliferation of cells in a healing process of wounds, drugs which promote or stimulate migration, differentiation and proliferation of cells participates in wound healing can be therapeutic agents for wounds. Lysozyme chloride, solcoseryl and the like are known as these therapeutic agents for wounds.
However, existing therapeutic agents for wounds entail the problems that the agents do not exhibit sufficient promotive actions on wound healing and cannot recover the wounds completely for a short period. These problems are considered to be due to small contribution of these agents to recoverage of epidermis, synthesis of collagen, improvement of peripheral circulation, granulation formation, angiogenesis or the like, which is an important factor in the healing process of wounds.
Substance P analogs are polypeptides consisting of three to twelve amino acids which are disclosed specifically in U.S. Pat. No. 3,862,114, and these polypeptides are known to have hypotensive actions. Substance P, which is one of the substance P analogs, is a polypeptide released and formed from a neural terminal, is a polypeptide consisting of eleven amino acids represented by the formula of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 1) and is known to exhibit vasodilation, smooth muscle contraction, secretion promotion of salivary gland, a diuretic action and the like. In an ophthalmological field, there were reported an effect of substance P on improving abnormal secretion of conjunctival goblet cells in ophthalmic disorders (WO 95/13087), kinetics of substance P in inflammation such as keratitis (J. Jpn. Ophthalmol. Soc., 91, 982–987 (1987), J. Jpn. Ophthalmol. Soc., 92, 448–452 (1988)) and the like. Further, Japanese Laid-open Patent Publication No. 17489/1998 discloses that Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 2) (hereinafter referred to as “FGLM”), which is a tetrapeptide on a C-terminal side of substance P, has an effect as a therapeutic agent for corneal disorders.
On the other hand, an insulin-like growth factor is one of factors which adjust growth of normal human cells such as an epidermal growth factor, a fibroblast growth factor, a platelet-derived growth factor and a transforming growth factor and is classified into two groups, i.e., insulin-like growth factor-I (hereinafter referred to as “IGF-I”) and insulin-like growth factor-II (hereinafter referred to as “IGF-II”). It was reported that IGF-I stimulates proliferation of thyroid cells (J. Biol. Chem., 264, 18485–18488 (1989)), IGF-II adjusts growth and differentiation of muscle (Hum. Mol. Genet., 3, 1117–1121 (1994)), and the like.
However, there have been no report relating to actions of the substance P analogs and the insulin-like growth factor on skin disorders.
From these facts, it is an interesting subject to combine the substance P analog with the insulin-like growth factor and to perform pharmacological tests on epidermis in order to study promotive effects on epidermal extension and promotive effects on skin wound healing.